Trastuzumab Deruxtecan Cuts Risk of Disease Progression or Death by 50% for Patients With HER2-Low Metastatic Breast Cancer

Classifying breast cancer along the familiar lines of human epidermal growth factor receptor 2 (HER2)-positive or HER2-negative may be a thing of the past, following the June 5 release of landmark findings. These show that trastuzumab deruxtecan (Enhertu) offered significant benefits in both progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in a group of patients with HER2-low metastatic breast cancer.¹

Data from the DESTINY-Breast04 study (NCT03734029), published in the New England Journal of Medicine,1 drew a standing ovation during the plenary session of the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. The findings show that trastuzumab deruxtecan, already approved in certain unresectable or metastatic HER2-positive breast cancer or gastric cancers,² reduced the risk of disease progression or death by 50% compared with chemotherapy for HER2-low patients with both hormone receptor (HR)-positive and HR-negative disease.

Trastuzumab deruxtecan, jointly developed by Daiichi Sankyo and AstraZeneca, is among a group of therapies known as antibody-drug conjugates (ADCs), which connect monoclonal antibodies to tumor cells with a “linker,” causing a more targeted and potent effect on cancer. In this case, the well-known trastuzumab, which binds to HER2 receptors, works with deruxtecan to become embedded in the cancer cell, disrupting the cell’s DNA and leading to cell death.³

DESTINY-Breast04 was a phase 3 trial of previously treated patients with metastatic HER2-low disease. It had a primary end point of PFS in patients with HR-positive disease. Secondary end points included PFS based on blinded independent central review of all randomly assigned patients, including those with HR-positive and -negative disease, and OS in HR-positive patients and OS in all patients.²

Results from the trial showed the following:

• Of the 557 randomly assigned patients, 494 (88.7%) had HR-positive disease and 63 (11.3%) had HR-negative disease.
• In the HR-positive group, median PFS was 10.1 months in the trastuzumab deruxtecan group vs 5.4 months for those receiving chemotherapy (physician’s choice), for a hazard ratio (HR) of 0.51 (P < .001). OS in this group was 23.9 months for the study drug vs 17.5 months for chemotherapy (HR, 0.64; P = .003).
• Among all patients, median PFS was 9.9 months for trastuzumab deruxtecan and 5.1 months for chemotherapy (HR, 0.50; P < .001).
• Adverse events of grade 3 or higher were lower in the study drug group at 52% vs 67.4% in the chemotherapy group.
• Of concern in patients receiving ADCs, interstitial lung disease or pneumonitis was seen in 12.1% of the study drug group; 0.8% of patients died.

Another concern raised was the small number of Black and Hispanic patients enrolled in the trial, and several commenters called for ongoing studies to determine how these patients fared with the therapy.

During a press briefing and the plenary session, Shanu Modi, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and the trial’s principal investigator, and experts from ASCO pronounced the results as game changing in breast cancer.

As Modi explained, “We currently define the HER2 status of breast cancers in a binary model, where HER2-positive breast cancers driven by the oncogene are treatable with currently available HER2-positive targeted therapies and HER2-negative breast cancers are not.”

In reality, it’s not that clear cut. Within the HER2 group some patients have low levels of HER2 expression that may still be targetable, but thus far therapies have proved ineffective. For this reason these patients have been classified as HER2 negative for treatment.

ADCs, which Modi called next-generation targeted therapies, offer a delivery system that creates a “bystander” effect, which also targets cells in the immediate vicinity of the tumor. Thus, patients with HER2-low disease see responses unlike any seen previously, said Modi and ASCO commenter Jane L. Meisel, MD, of Winship Cancer Institute at Emory University in Atlanta, Georgia.

The experience with trastuzumab deruxtecan has been remarkable, Meisel said. “Everyone who’s used it in our clinic undoubtedly has seen some patients—even with significant burdens of disease—have their cancer melt away with this agent,” she said. “What this trial does is really extend the benefits of this agent to a whole new group of patients.”

Modi concluded, “These results established [that patients with] HER2-low metastatic breast cancer is a targetable population of breast cancer, with trastuzumab deruxtecan as a new standard of care in this setting.”

Asked by The American Journal of Managed Care® to highlight what she found compelling about the results, Debra Patt, MD, PhD, MBA, executive vice president for health care policy and strategic initiatives at Texas Oncology and an expert in breast cancer treatment, cited 3 things:

• Among patients with HER2-low disease, there is a survival benefit of receiving trastuzumab deruxtecan vs physician’s choice chemotherapy.
• The population that stands to benefit is large. “As we understand it, about 55% of patients with advanced breast cancer may benefit from this therapeutic intervention,” Patt said.
• The toxicity profile of patients who received trastuzumab deruxtecan was lower than that of patients who received standard chemotherapy.
  

“What this tells us, in summary, is that among patients who have HER2-low breast cancer and have been treated previously with a chemotherapy, if they receive trastuzumab deruxtecan, they are likely to have an overall survival benefit and lower toxicity as opposed to if they receive chemotherapy,” said Patt, who is also a member of the Evidence-Based Oncology™ editorial board.

ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, FACP, FASCO, added that the pathology of breast cancer would have to be redefined, based on the findings in DESTINY-Breast04.

Patt agreed. “No longer can we simply say that someone is HER2-positive or HER2-negative, but the appreciation of HER2 low becomes really important as these patients clearly benefit from therapeutic intervention,” she said. “As we rethink this, we need to understand better and work with our pathologists [regarding] how we can make sure that we represent [patients who are] IHC [immunohistochemistry] 1 positive or IHC 2 positive, or this HER2-low population, in a systematic way to make sure patients can benefit from particular treatments.”

During the plenary session, Patricia LoRusso, DO, professor, Yale School of Medicine in New Haven, Connecticut, called for better tools to evaluate HER2 status during remarks after Modi’s presentation. Patt concurred with this as well.

“We need to understand different limitations of assessment; for example, when the bone is biopsied, can there be false-negative results from the decalcification process? These are specifics that we need to understand as we try to ensure that each patient might benefit from particular therapeutic innovations in clinic,” Patt said. 

References
1. Modi S, Jacot W, Yamashita J, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2203690
2. Enhertu reduced the risk of disease progression or death by 50% vs chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive and HR-negative disease. News release. AstraZeneca. June 5, 2022. Accessed June 13, 2022. https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-efficacy-results-in-her2-low-breast-cancer.html
3. Walko CM, West HJ. Antibody drug conjugates for cancer treatment. JAMA Oncol. 2019;5(11):1648. doi:10.1001/jamaoncol.2019.3552